This application proposes to assess the acute and chronic effects of methamphetamine (METH) and 3,4-methylenedioxymethamphetamine (MDMA) on dopamine (DA) and serotonin (5-HT) terminal function and evaluate the relationship between DA and 5-HT neurotoxicity. We will first compare the effects of METH and MDMA on monoamine terminal function acutely in mouse brain slices. Then we will evaluate terminal function recovery following a repeated administration paradigm. Voltammetry at carbon fiber electrodes will be used to measure release and uptake of DA and 5-HT in brain slices. With the use of the DA and the 5-HT transporter knockout mouse lines, and the selective neurotoxins phentermine and fenfluramine, we will evaluate whether DA influences 5-HT neurotoxicity, and vice versa. The research proposed will provide valuable insights into the differential long-term impact of amphetamine derivatives on monoamine systems and the potential interactions between DA and 5-HT in inducing neurotoxicity.